Head & neck tumors are highly vascularized malignancies with poor survival rates with current-therapiesr It-is known that vascular endothelial growth factor (VEGF) is a strong inducer of tumor angiogenesis, and that VEGF enhances endothelial cell survival and resistance to treatment by upregulating the expression of Bcl-2. We have recently demonstrated that Bcl-2 functions as a pro-angiogenic signaling molecule, in addition to its well-known anti-apoptotic effect (Karl et a/., 2005). Inhibition of VEGF signaling with an antibody (e.g. Avastin), or with an inhibitor of one its receptors (e.g. PTK787) results in selective ablation of tumor blood vessels and inhibition of tumor growth. These results demonstrate that the VEGF/Bcl-2 pathway is critical for the maintenance of tumor vasculature. Structure based 30-database searching led to the development of novel small molecule inhibitors of Bcl-2 (TW-37 and TM-1252). We have demonstrated that TW-37 induces apoptosis of head & neck tumor cells and neovascular endothelial cells (but not dermal fibroblasts) in vitro, and that TW-37 is anti-angiogenic in vivo (Zeitlin et a/., 2006). This work demonstrated that a small molecule inhibitor of Bcl-2 represents a novel class of drugs that induces tumor cell apoptosis and is anti-angiogenic, two distinct and perhaps synergistic anti-tumor effects. However, we do not know the effect of a small molecule inhibitor of Bcl-2 on the resistance of head & neck tumors to radiation therapy and to conventional chemotherapy, and what is the better treatment sequence and timing. The broad long-term goals of this translational project are to understand the effect of therapeutic inhibition of Bcl-2 on the clinical outcome of patients with head & neck cancer. The objectives of this application are to evaluate the effect of a small molecule inhibitor used in a metronomic regimen (low dose, high frequency) in combination with radiation therapy and Cisplatin on angiogenesis in vitro and in vivo, and on the growth of head & neck tumors in vivo. We plan to accomplish these objectives by studying mechanisms involved in the process of small molecule inhibitor of Bcl-2-mediated endothelial cell and tumor cell apoptosis, when used in combination with ionizing radiation and chemotherapy. The SCID Mouse Model of Human Angiogenesis and in vivo bioluminescence will be used to evaluate the effect of timing and sequence of treatment on angiogenesis and tumor growth. And a Phase I clinical trial wilj be conducted in patients that were previously treated with radiation therapy and standard chemotherapy to begin evaluation of the safety and efficacy of a small molecule inhibitor of Bcl-2 for treatment of head & neck cancer. The knowledge generated here will enhance pur understanding about the function of Bcl-2 in head & neck tumor angiogenesis and growth, and will demonstrate if therapeutic blockade of Bcl-2 function affects resistance to ionizing radiation and chemotherapy.